Fate of reactive axonal swelling induced by head injury

Povlishock, J. T.; Becker, D. P.

doi:10.1097/00001199-198806000-00012

Cited by 40 publications

(57 citation statements)

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“…Unique to traumatic axonal injury, this immediate transport interruption may reflect mechanical disruption of the axonal cytoskeleton, such as breaking of microtubules due the dynamic aspect of the deformation (Smith et al, 1999b;Tang-Schomer et al, 2010). Ultimately, these axons may disconnect at distal points of swellings, which triggers degeneration within days after injury, as characterized by Povlishock and colleagues (Povlishock and Becker, 1985;Grady et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…For moderate to severe TBI, diffuse axonal injury (DAI) is well recognized as one of the most common and important pathologies (Adams et al, 1982(Adams et al, ,1989Graham et al, 1988;Povlishock, 1992;Povlishock and Becker, 1985;Povlishock and Katz, 2005;Povlishock et al, 1983;Smith and Meaney, 2000a). However, by definition, mTBI alone is non-fatal, thereby severely restricting the opportunity for neuropathological examination.…”

Section: Introductionmentioning

confidence: 99%

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Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Browne

Chen²,

Meaney³

et al. 2011

Journal of Neurotrauma

217

172

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Until recently, mild traumatic brain injury (mTBI) or ''concussion'' was generally ignored as a major health issue. However, emerging evidence suggests that this injury is by no means mild, considering it induces persisting neurocognitive dysfunction in many individuals. Although little is known about the pathophysiological aspects of mTBI, there is growing opinion that diffuse axonal injury (DAI) may play a key role. To explore this possibility, we adapted a model of head rotational acceleration in swine to produce mTBI by scaling the mechanical loading conditions based on available biomechanical data on concussion thresholds in humans. Using these input parameters, head rotational acceleration was induced in either the axial plane (transverse to the brainstem; n = 3), causing a 10-to 35-min loss of consciousness, or coronal plane (circumferential to the brainstem; n = 2), which did not produce a sustained loss of consciousness. Seven days following injury, immunohistochemical analyses of the brains revealed that both planes of head rotation induced extensive axonal pathology throughout the white matter, characterized as swollen axonal bulbs or varicosities that were immunoreactive for accumulating neurofilament protein. However, the distribution of the axonal pathology was different between planes of head rotation. In particular, more swollen axonal profiles were observed in the brainstems of animals injured in the axial plane, suggesting an anatomic substrate for prolonged loss of consciousness in mTBI. Overall, these data support DAI as an important pathological feature of mTBI, and demonstrate that surprisingly overt axonal pathology may be present, even in cases without a sustained loss of consciousness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Browne

Chen²,

Meaney³

et al. 2011

Journal of Neurotrauma

217

172

View full text Add to dashboard Cite

show abstract

“…1), the progressive swelling of these structures has been shown to lead to disconnection. 3,8,21,[27][28][29][30] In contrast, a series of swellings along otherwise intact axons represent ''axonal varicosities.'' 31 This common pathological profile found in acute TBI may reflect a process whereby transport is only partially interrupted at multiple sites along the axon's length, producing the string-of-beads appearance, in contrast with presumed complete interruption at one site forming singular axonal bulbs.…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

“…2). 20,21,27,28 Interestingly, in the most catastrophic axonal injuries, there is now emerging evidence that massive local ionic dysregulation triggers a dramatic local cytoskeletal collapse so severe as to reverse axonal transport and blunt the progression of any subsequent swelling (Fig. 2).…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

“…7,8 Although these tissue deformations rarely lead to disconnection of axons at the time of injury, they nonetheless can precipitate a spectrum of focal pathological abnormalities in axons that can lead to delayed secondary disconnection or sustained dysfunction. 3,8,18,21,27,44,51,54,59,60 The selective injury to axons in TBI appears to be related to their viscoelastic nature reflecting a unique ultrastructure and collective anisotropic arrangement in tracts. Within axons, microtubules and neurofilaments are arranged in a linear fashion with perpendicular protein projections and cross-links.…”

Section: Biomechanics Of Daimentioning

confidence: 99%

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Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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Bilateral growth-related protein expression suggests a transient increase in regenerative potential following brain trauma

et al. 2000

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The potential of mature central nervous system (CNS) neurons to regenerate after injury represents a fundamental issue in neurobiology. The regional expression of proteins associated with axonal elongation, such as microtubule-associated protein 1B (MAP1B), its phosphorylated isoform (MAP1B-P), growth-associated protein 43 (GAP-43), and polysialylated neural cell-adhesion molecule (PSA-NCAM), was examined using immunohistochemistry from 24 hours to 2 months following lateral fluid percussion brain injury of moderate severity (2.4-2.6 atmospheres) in anesthetized rats. Uninjured (control) rats were subjected to anesthesia and surgery without injury or were subjected to anesthesia alone. Within the site of maximal injury, only increases in MAP1B and MAP1B-P were observed. Increased immunoreactivity was observed bilaterally for all growth-related proteins that were evaluated. By 24 hours postinjury, MAP1B and MAP1B-P increased within the cortex (P < 0.01) and the hippocampus (P < 0.001), whereas MAP1B-P also was elevated in the thalamus (P < 0.05). Within the dentate gyrus, increased immunoreactivity was observed for all proteins examined. By 48 hours postinjury, GAP-43 was elevated bilaterally within the inner molecular layers of the dentate gyrus (P < 0.005) and within the stratum lacunosum moleculare (P < 0.01), the stratum radiatum (P < 0. 005), and the stratum oriens (P < 0.05) of the hippocampus. Increased numbers of PSA-NCAM-labeled neurons were observed in the granule cell layers of the dentate gyrus from 48 hours through 2 weeks postinjury (P < 0.0005). The bilateral nature of increased expression of growth-related proteins differs from unilateral patterns of neuronal degeneration previously characterized for the lateral fluid-percussion model of brain injury. Taken together, these results suggest the existence of a temporary posttraumatic state in which the CNS may have increased regenerative potential. Enhancement of such a response may be one therapeutic strategy in treating CNS injury.

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Fate of reactive axonal swelling induced by head injury

Cited by 40 publications

References 0 publications

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Therapy Development for Diffuse Axonal Injury

Bilateral growth-related protein expression suggests a transient increase in regenerative potential following brain trauma

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